Primary biliary cirrhosis (PBC) is an enigmatic autoimmune disease characterized by female predominance, high titer anti- mitochondrial antibodies (AMA), small bile duct destruction, and liver failure. Our group was the first to clone and identify the mitochondrial antigens, a family of phylogenetically conserved 2- oxo acid dehydrogenase proteins recognized by T and B cells in PBC. In addition, recent data has provided us with the basis for the following working hypotheses. We submit that PBC is most likely the result of an inappropriate or malcontrolled response to an environmental (either chemical or biological) insult. The initiating insult in PBC could be either a urinary tract infection (UTI) or an exposure to halogen containing chemicals. In the case of UTI's, there are high degrees of homology between the mitochondrial proteins present in micro-organisms that characteristically cause UTI's and their eukaryotic (i.e. human) analogs. Alternatively, the liver-based metabolism of halogenated hydrocarbons as xenobiotics generates activated halogen containing intermediates that react to form halogen modified proteins. In both, UTIs and halogenated chemical exposures, the introduction of these foreign proteins may initiate an immunological response that results in the immune system inappropriately targeting self proteins. These insults, which appear to be necessary but are not sufficient to elicit an autoimune response, given their widespread occurrence, needs to occur in conjunction with other disease associated contributory factors (i.e. genetic background) to produce PBC. We propose to take advantage of our strengths, including a nationwide network of PBC researchers, to accomplish this goal. We will collect and analyze data on demographics (race/ethnicity, socio-economic status, place of birth), medical history, reproductive history (parity, birth outcomes/complications, fertility problems, oral contraceptive use), menstrual history (age at menarche, age at menopause, average cycle length, cycle regularity) and lifestyle factors (smoking, physical activity, occupation and occupational exposures) using a questionnaire that we have tested in a preliminary study of 201 patients and 171 unaffected siblings. The project data will be collected from a sample of 2000 cases from 17 medical centers around the country and an equal number of matched (on age, gender and residence) random-digit dialed controls. The proposed study would be the first comprehensive epidemiologic study of PBC to be conducted in the United States, and directed at testing our thesis in the hope of improving our understanding of this serious disease and potentially identifying preventive measures.